Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof

Abstract

Progesterone receptor modulators of formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein. These compounds are useful for contraception and hormone replacement therapy. Also provided are products containing these compounds.

1. A method of treating benign and malignant breast neoplastic disease, adenocarcinomas or estrogen related breast carcinomas, said method comprising administering, said method comprising administering to a female of child-bearing age, a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of:
 H, 
 CN, 
 C(O)—C 1 -C 6  alkyl, C(O)—C 3 -C 8  cycloalkyl, C(O)-substituted C 1 -C 6  alkyl, C(O)-aryl, C(O)-substituted aryl, C(O)-heteroaryl, C(O)-heterocycle, C(O)—C 3 -C 6  alkenyl, C(O)—C 3 -C 6  alkynyl, C(O)-substituted C 3 -C 6  alkenyl, C(O)-substituted C 3 -C 6  alkynyl, 
 C(O)O—C 1 -C 6  alkyl, C(O)O—C 3 -C 8  cycloalkyl, C(O)O-substituted C 1 -C 6  alkyl, C(O)O-aryl, C(O)O-substituted aryl, C(O)O-heteroaryl, C(O)O-heterocycle, C(O)O—C 3 -C 6  alkenyl, C(O)O—C 3 -C 6  alkynyl, C(O)O—C 3 -C 6  substituted alkenyl, C(O)O—C 3 -C 6  substituted alkynyl, 
 C(O)NH—C 1 -C 6  alkyl, C(O)NH—C 3 -C 8  cycloalkyl, C(O)N-di-C 3 -C 8  cycloalkyl, C(O)N-di C 1 -C 6  alkyl, C(O)N-di-substituted C 1 -C 6  alkyl, C(O)NH-substituted C 1 -C 6  alkyl, C(O)NH-aryl, C(O)N-di-aryl, C(O)NH-substituted aryl, C(O)N-di-substituted aryl, C(O)NH-heteroaryl, C(O)N-di-heteroaryl, C(O)NH-heterocycle, C(O)N-di-heterocycle, C(O)NH—C 3 -C 6  alkenyl, C(O)NH—C 3 -C 6  alkynyl, C(O)NH-substituted C 3 -C 6  alkenyl, and C(O)NH-substituted C 3 -C 6  alkynyl; or 
 
 R 1  is a linking group to a second structure of formula I to form a dimer of formula I, said linking group is a C(O)— group; 
 R 2  is selected from the group consisting of H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl; 
 provided that both R 1  and R 2  are not H; 
 provided that where R 1  is C(O) substituted aryl, R 2  is not H; 
 provided that when R 1  is H and R 7  is H, R 2  is not C 1 -C 6  alkyl; 
 R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, O—C 1 -C 6  alkyl, O—C 1 -C 6  substituted alkyl, aryl, heteroaryl, heterocycle, substituted aryl, substituted heteroaryl, and substituted heterocycle; and 
 R 7  is selected from the group consisting of H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and substituted C 3 -C 6  cycloalkyl. 
 
     
     
       2. The method according to  claim 1 , wherein:
 R 1  is ON; 
 R 2  is H or C 1 -C 6  alkyl; 
 R 3 , R 4 , R 5  and R 6  are, independently, selected from the group consisting of H, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, O—C 1 -C 6  alkyl, and O—C 1 -C 6  substituted alkyl; and 
 R 7  is H or C 1 -C 6  alkyl. 
 
     
     
       3. The method according to  claim 1 , wherein:
 R 1  is ON; 
 R 2  is H; 
 R 3 , R 4 , R 5  and R 6  are, independently, selected from the group consisting of H, halogen, C 1 -C 6  alkyl, and O—C 1 -C 6  alkyl; and 
 R 7  is H or C 1 -C 6  alkyl. 
 
     
     
       4. The method according to  claim 1 , wherein:
 R 1  is C(O)C 1 -C 6  alkyl, C(O)—C 3 -C 6  cycloalkyl or C(O); 
 R 3 , R 4 , R 5  and R 6  are, independently, selected from the group consisting H, halogen, C 1 -C 6  alkyl, and O—C 1 -C 6  alkyl; and 
 R 7  is H or C 1 -C 6  alkyl. 
 
     
     
       5. The method according to  claim 4 , wherein:
 R 1  is C(O)C 1 -C 4  alkyl or C(O)—C 3 -C 6  cycloalkyl; 
 R 3 , R 4 , R 5  and R 6  are H; and 
 R 7  is C 1  alkyl. 
 
     
     
       6. The method according to  claim 1 , wherein:
 R 1  is selected from the group consisting of CO(NH 2 ), ON, C(O)-heteroaryl, wherein the heteroaryl is a furan, C(O)aryl, wherein the aryl is a phenyl ring, and C(O)O—C 1 -C 3  alkyl. 
 
     
     
       7. The method according to  claim 1 , wherein R 1  is a C(O) linking group to a second structure of formula (I) to form a dimer thereof. 
     
     
       8. The method according to  claim 1 , wherein R 3  is selected from the group consisting of H, C 1 -C 3  alkyl, a halogen selected from the group consisting of F and Cl, and O—C 1 -C 3  alkyl. 
     
     
       9. The method according to  claim 1 , wherein R 4  is selected from the group consisting of H and O—C 1 -C 3  alkyl. 
     
     
       10. The method according to  claim 1 , wherein R 5  is selected from the group consisting of H, C 1 -C 3  alkyl, a halogen selected from the group consisting of F and Cl, and O—C 1 -C 3  alkyl. 
     
     
       11. The method according to  claim 1 , wherein R 6  is selected from the group consisting of H and halogen, wherein the halogen is F. 
     
     
       12. The method according to  claim 1 , wherein R 7  is C 1  alkyl. 
     
     
       13. The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-furamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-3-methylbutanamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylpropanamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propanamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]butanamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]acetamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]benzamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyclobutanecarboxamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyclohexanecarboxamide; 
       N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylacrylamide; 
       Ethyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate; 
       Isobutyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate; 
       N,N-bis[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]urea; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylphenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-ethylphenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-propylphenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-isopropylphenyl]cyanamide; 
       [2-chloro-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyanamide; 
       [2-fluoro-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methoxyphenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-methoxyphenyl]cyanamide; 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-methylphenyl]cyanamide; and 
       [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methylcyanamide. 
     
     
       14. The method according to  claim 1 , wherein said compound is administered in a pharmaceutical composition. 
     
     
       15. The method according to  claim 14 , wherein said composition further comprises an estrogen or progestin.